Journal of Biological Chemistry
Volume 272, Issue 6, 7 February 1997, Pages 3324-3329
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Cell Biology and Metabolism
Inhibition of Carnitine Palmitoyltransferase I Augments Sphingolipid Synthesis and Palmitate-induced Apoptosis*

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To identify cell death-induced genes, we employed a subtractive hybridization approach and isolated a cDNA encoding a mouse homolog of carnitine palmitoyltransferase I (CPT I), an enzyme that resides at the outer mitochondrial membrane and facilitates passage of long-chain fatty acids into mitochondria for β-oxidation. Induced expression of CPT I mRNA was observed upon programmed cell death in the murine hematopoietic cell lines LyD9 and WEHI-231. To elucidate the role of CPT I in programmed cell death, we examined the effects of long-chain fatty acids and found that the addition of palmitate or stearate to cultured cells led to activation of a death program with a morphology resembling that of apoptosis. Other naturally occurring fatty acids, including myristate and palmitoleate, had no effect. Since both palmitate and stearate are sphingolipid precursors, the effect of these fatty acids on sphingolipid metabolism was tested. Our results indicate that apoptosis induced by palmitate or stearate is correlated with de novo synthesis of ceramide. Inhibition of CPT I by etomoxir enhanced palmitate-induced cell death and led to a further increase in ceramide synthesis.

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*

This work was supported in part by grants from the Ministry of Education, Science, and Culture of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by the Canon Foundation (Europe), the Japanese German Center (Berlin), Japan Tobacco Inc., and the Japan Society for the Promotion of Science.